To investigate the outcomes and recurrences of pT1b esophageal adenocarcinoma (EAC) following endoscopic mucosal resection (EMR) and associated treatments.

Patients undergoing EMR with pathologically confirmed T1b EAC at two academic referral centers were retrospectively identified. Patients were divided into 4 groups based on treatment following EMR: Endoscopic therapy alone (group A), endoscopic therapy with either chemotherapy, radiation or both (group B), surgical resection (group C) or no further treatment/lost to follow-up (< 12 mo) (group D). Pathology specimens were reviewed by a central pathologist. Follow-up data was obtained from the academic centers, primary care physicians and/or referring physicians. Univariate analysis was performed to identify factors predicting recurrence of EAC.

Fifty-three patients with T1b EAC underwent EMR, of which 32 (60%) had adequate follow-up ≥ 12 mo (median 34 mo, range 12-103). There were 16 patients in group A, 9 in group B, 7 in group C and 21 in group D. Median follow-up in groups A to C was 34 mo (range 12-103). Recurrent EAC developed overall in 9 patients (28%) including 6 (38%) in group A (median: 21 mo, range: 6-73), 1 (11%) in group B (median: 30 mo, range: 30-30) and 2 (29%) in group C (median 21 mo, range: 7-35. Six of 9 recurrences were local; of the 6 recurrences, 5 were treated with endoscopy alone. No predictors of recurrence of EAC were identified.

Endoscopic therapy of T1b EAC may be a reasonable strategy for a subset of patients including those either refusing or medically unfit for esophagectomy.

Due to the inherent morbidity and rare mortality associated with esophagectomy and lymph node dissection, endoscopic eradication therapy [including endoscopic mucosal resection (EMR) and ablative techniques] has been increasingly used as a safe, effective and potentially curative organ-sparing procedure to treat high grade dysplasia (Tis lesions) and intramucosal esophageal cancer (T1a lesions)[1-5]. When complete resection or eradication of T1a cancers is confirmed, disease is generally considered cured due to the low rate of reported lymph node metastasis (< 2%) in these patients[6]. Tumors that penetrate the submucosa of the esophagus (T1b cancers), however metastasize to regional lymph nodes in up to 30% of cases and the likelihood for metastases increases the further the tumor penetrates from the first third (sm1) into the lower two thirds (sm2 and sm3) of the submucosal layer[7-11]. Therefore, endoscopic eradication therapies (EET) have generally not been employed in patients with T1b cancers.

The use of EET for primary treatment of T1b tumors was initially reported in patients with “low risk” submucosal esophageal cancers (macroscopically polypoid or flat, invasion limited to the upper 1/3 of the submucosa, no invasion of the vessels or lymphatic system, well to moderate tumor differentiation); this has more recently been updated in a larger series (n = 66) from the same group with similar characteristics showing recurrent or metachronous carcinomas developed in 19% of patients with an estimated 5 year survival rate of 84%[12,13]. A study from two referral centers in the Netherlands examined EET of deep T1a and T1b EAC (n = 75) with an overall recurrence rate of 9%[14]. A study from a tertiary center in the United States reported a group of patients (n = 29) with T1b EAC with sm1 (46%) and sm2-3 (54%) invasion that underwent either EET, chemo/radiation or a combination of both and showed mean survival of 34.8 mo with a 38% mortality rate[15].

To our knowledge, there are no studies examining the outcomes and predictors of disease recurrence in patients with pathologically staged T1b esophageal cancer treated with EET alone, surgery, or adjuvant therapy following endoscopic resection. Identification of predictive factors for recurrence and outcomes following endoscopic therapy in this population would help to identify and tailor appropriate treatment. For this reason, we aimed to (1) retrospectively evaluate the clinical outcomes of pT1b esophageal cancers following EMR; (2) to compare the recurrence rates of cancer when patients are treated with EET alone, EET in association with chemotherapy, radiation therapy or both and surgical resection; and (3) to evaluate the predictors of recurrence of T1b esophageal cancer following EMR.

Sixty patients who underwent EMR were found to have pT1b esophageal cancer, including 53 (88%) with adenocarcinoma and 7 (12%) with squamous cell carcinoma. Of the 53 patients with adenocarcinomas, 32 patients (60%) had adequate follow-up after EMR of ≥ 12 mo (median 34 mo, range 12-103). There were 16 patients in group A, 9 patients in group B, 7 patients in group C and 21 patients in group D (8 with no further treatment and 13 without required 12 mo follow-up). Demographics, EMR method (cap vs band), pathology findings and follow-up are summarized in Table 1. Pathology in patients who underwent esophagectomy (group C) showed no residual dysplasia or malignancy in 2, adenocarcinoma with negative nodes in 1, dysplasia in 3 and 1 with unknown findings.

No recurrence of carcinoma developed in 23 patients (72%) during a median follow-up of 31 mo (range 12-103). Recurrent adenocarcinoma developed in 9 (28%) patients among all 3 groups. There was no statistically significant differences between recurrences in group A (n = 6; 38%), group B (n = 1; 11%) and group C (n = 2; 29%). Median time to recurrence was 21 mo (range 6-73) in group A, 30 mo in group B, and 9 mo (range 8-10) in group C. Of the recurrences in group A, 5 were local and 1 was metastatic. These local recurrences in group A were treated with further EET alone in two, EET and radiation in one, EET with chemotherapy with radiation in one and radiation in one. The single metastatic recurrence in group A was treated with chemotherapy and radiation. The single recurrence in group B was metastatic and had no further treatment. The two recurrences in group C were local in one and metastatic in one. The local recurrence in group C was treated with chemotherapy and the metastatic recurrence in group C was treated with local resection of a hepatic metastasis. No predictors of recurrence of adenocarcinoma were identified on univariate analysis (Table 2).

Of the 32 patients in groups A, B and C, 7 died within 3 years of EMR giving an overall 3 year mortality for all causes of 22%. Specifically within each group, 3 year mortality rates were 13% in group A (2/16), 44% in group B (4/9), and 14% in group C (1/7).

EUS was performed prior to EMR in 51 (96%) of the 53 patients with T1b EAC. T staging accuracy (for T1 malignancy) on EUS for pT1b tumors overall was 92%; specifically for pT1sm1 tumors was 92% and for pT1sm2/3 tumors was 92% (Table 3).

Endoscopic therapy is an alternative to esophagectomy for mucosal EAC in select populations[1] and has been included in national guidelines as a curative form of treatment[16]. More recently, “low risk” T1b EAC have been treated with EET as primary therapy in Germany with recurrence rates ranging from 19% to 28% and estimated five-year survival rates up to 84%[12,13]. Two small studies from the United States (n = 15) and the Netherlands (n = 18) showed a recurrence rate of 21% and 17% respectively, with all recurrences in the latter study having initial sm2/3 depth of invasion[14,15].

In our study, we aimed to retrospectively evaluate and compare outcomes of various treatments for T1b EAC after EMR and to evaluate predictors of recurrence after those treatments. We found an overall recurrence rate of 28%, which was not statistically different between those treated with endotherapy alone (38%), chemotherapy, radiation or both (11%) or those undergoing esophagectomy (29%). The overall observed rate of recurrence in our study for those undergoing EET alone is higher than previously reported in patients undergoing EET as primary therapy (Table 4). These differences likely reflect differences in population between most other series (which included primarily low risk T1bsm1 EAC) and our study which evaluated outcomes for all T1b patients. The rate of recurrence in our study does compare favorably to that previously reported for a small cohort of patients with sm2/3 invasion of 33%[14].

We found that most recurrences following EMR in those treated at least partly endoscopically (groups A and B) were localized. Of the patients who underwent EET alone, there were 6 recurrences (38%), five of which were localized to the esophagus with only 1 having metastatic disease 21 mo following EMR. Of the patients who underwent EET + chemotherapy and/or radiation, 1 (11%) had metastatic recurrence 30 mo after resection. Therefore, EET with or without chemotherapy or radiation, may be a reasonable initial treatment strategy for a subset of patients with T1b EAC, especially those that refuse or are unfit for surgical intervention due to medical comorbidities or home support since most recurrences appear to be localized.

In those that underwent esophagectomy, we identified 2 recurrences out of 7 patients (29%). Our recurrence rate is similar to a recent retrospective study including 26 patients with T1b EAC undergoing surgical resection which showed a 23% recurrence rate[17]. Recurrence or metastatic disease discovered after resection may be related to micrometastatic disease that was unable to be identified prior to esophagectomy.

Overall, we found a 3-year survival rate of 78% when evaluating the patients in our study; more specifically a rate of 87% in those treated with EET only and 56% in those treated with EET + chemotherapy and/or radiation. When combining those treated at least partly endoscopically, the survival rate at 3 years was 76%. Manner et al[13] previously have shown an estimated 5-year survival rate of 84% in those treated with EET with “low risk” T1b. Our lower survival rate is likely reflected in our patient population, as we evaluated all patients with T1b EAC and not only those with “low risk” disease. Tian et al[15] reported on a group of patients (n = 29) more similar to our cohort including “low risk” and higher risk T1b EAC patients [sm1 (46%) and sm2-3 (54%) invasion] that underwent either EET, chemo/radiation or a combination of both and showed a survival rate of 72% at mean 34.8 mo.

We failed to identify any individual predictors of cancer recurrence in this population. A previous retrospective study with 39 patients with T1b EAC treated with EET alone showed decreased survival in patients with older age and lymphovascular invasion, although it did not specifically assess for predictors of cancer recurrence[18]. In our study, we were unable to identify lymphatic and perineural invasion as predictors of recurrence.

A recent prospective study from Germany evaluated the risk of lymph node metastases when comparing “low risk” (sm1 invasion) to “high risk” (sm2/3 invasion) T1b EAC in patients treated both surgically and with EET, and found a 2% risk of lymph node metastasis in pT1bsm1 tumors and 9% in pT1bsm2/3 tumors, which is lower than has generally been reported in prior studies[19]. In our study which includes both sm1 and sm2/3 invasion, we similarly found 6% of patients with metastatic lymph nodes either on initial staging or on surveillance (one each with sm1 and sm2/3 tumors).

Previous studies have shown excellent accuracy for staging both T1a and T1b esophageal cancers. Specifically, a previous meta-analysis showed good accuracy with area under the curve > 0.93 for both T1a and T1b esophageal cancers[20]. We also demonstrated overall diagnostic accuracy of 91% for pT1 lesions in our cohort.

Our study has several strengths including data from all T1b cancers removed by EMR from two tertiary care referral centers, re-review of all pathology by a single pathologist, and evaluation of outcomes of medical and surgical therapy for these patients. However, our study is limited by the number of patients who refused further therapy or were lost to follow-up which may limit the ability to compare outcomes from various treatments after resection.

In conclusion, our study shows that endoscopic therapy alone following EMR of a T1b cancer is associated with a recurrence rate of 38%. Therefore, treatment with adjuvant therapy appears reasonable in this population when possible. No particular variable is predictive of recurrence following EMR of T1b adenocarcinomas. Therefore, future research into the management and risk stratification of these patients after EMR is warranted.